Orally administered analgesic compositions containing nalbuphine

ABSTRACT

The present invention provides orally administered pharmaceutical compositions which contains an effective amount of free base or pharmaceutically acceptable salts of nalbuphine and/or nalbuphine ester, an oily substance, and a solubility-assisting agent. The oily substance is preferably sesame oil. The solubility-assisting agent is preferably benzyl benzoate. The pharmaceutical composition is useful as an analgesic. The compositions achieves a much higher bioavailability rate and yields much longer lasting effects on nalbuphine than other nalbuphine products currently in the market.

FIELD OF THE INVENTION

[0001] The present invention relates to novel analgesic pharmaceuticalcompositions containing free base or pharmaceutically acceptable saltsof nalbuphine and/or nalbuphine ester, an oily substance, and asolubility-assisting agent. In particular, the present invention relatesto orally administered nalbuphine and/or nalbuphine ester whichdemonstrates long lasting effect and greater bioavailability for painrelief in animals. The preferred oily substance is sesame oil. Thepreferred solubility-assisting agent is benzyl benzoate.

BACKGROUND OF THE INVENTION

[0002] Nalbuphine is a synthetic opiate agonist-antagonist that ischemically related to both naloxone, a narcotic antagonist, andoxymorphone, a potent narcotic analgesic. Nalbuphine simultaneouslyexhibits a dual action of agonism and antagonism towardsopiolds-receptors. Schmidt, W.F. et al., Drug Alcohol Depend., Vol. 14,page 339 (1985). Opiate receptors include mu, kappa, and delta, whichhave been reclassified by an International Union of Pharmacologysubcommittee as OP 1 (delta), OP2 (kappa), and OP3 (mu). Nalbuphine actson specific opiate-receptor subtypes: it is a potent mu-antagonist withless dysphoric effects, and its agonistic effects at kappa1- andkappa3-receptors provide analgesia.

[0003] Actions of nalbuphine at the kappa-receptors produce alterationsin the perception of pain as well as the emotional response to pain,possibly by altering the release of neurotransmitters from afferentnerves sensitive to painful stimuli. As an adjunct to anesthesia,nalbuphine protects against the hemodynamic responses to stress producedby surgery. Additionally, nalbuphine paradoxically produces opiatewithdrawal if administered to opiate-dependent patients, which is afunction of antagonism at the mu-receptor. Stimulation at mu-receptorproduces respiratory depression. However, nalbuphine causes lessrespiratory depression than morphine or related agents.

[0004] Nalbuphine is used to treat moderate to severe pain associatedwith acute and chronic medical disorders such as cancer, renal orbiliary colic, migraine or vascular headaches, and surgical pain.Nalbuphine is effective in control of severe and deep pain caused bycardiac, pulmonary, abdominal, osteopathia, and obstetrical surgery,severe burn injury, and the terminal stages of cancer via variousadministration routes, such as intramuscular, intravenous, intrathecal.The FDA approved nalbuphine in 1979.

[0005] Compared with conventional analgesics, nalbuphine drasticallyreduces induction of addiction and accretion of dosage in patients. Inaddition, Nalbuphine has decreased inhibition on respiratory system.Some evidence suggests that nalbuphine depressant effects on therespiratory system do not increase proportionately with increasingdoses, which makes the drug safer in patients at risk from respiratorydepression. However, the duration of Nalbuphine action is short, whichis not enough to relieve the severe pain.

[0006] Broekkamp et al., J. Pharm. Pharmacol., Vol. 40, 434 (1988),proposes a long-acting mechanism by ester-type prodrugs. The drugs areesterified with fatty acids of different carbon numbers resulting in anincrease in lipophilicity of the prodrugs. When the prodrugs are givenintramuscularly, the release rates are decreased and the duration ofaction is prolonged. Ester-type prodrugs are hydrolyzed by esterases inthe body to yield increase of mother compounds in vivo. Esterases existin many tissues and organs including blood, liver, heart, brain,kidneys, lungs, and muscles. The pharmacological effect and safety ofthe ester type prodrug and the mother compound are reported to be thesame.

[0007] Additionally, the conventional form of nalbuphine, nalbuphinehydrochloride (nalbuphine-HCl), is not practical for oraladministration, because the bioavailability through oral administrationis less than 5%. Thus, nalbuphine-HCl has not been made available in aform for oral administration. In a paper published in 1988 by HarrelsonJ. C. and Wong Y. J., Xenobiotica (1988), 18:1239-1247, the researchersfound that acetylsalicylate ester prodrug of nalbuphine improved thebioavailability through oral administration, which also masked thebitter taste of nalbuphine-HCl. However, the bioavailability of theacetylsalicylate ester prodrug is only 16%, which is still not effectiveenough for oral administration. In another paper published in 1988 byHussain, M. A. et al., J. Pharm. Sciences, 75:218-219 (1986), theresearchers found that buccal delivery could improve the bioavailabilityof the opioids prodrugs to as high as 35-50%. Nevertheless, buccaldelivery is not as convenient and acceptable as oral administration.Therefore, pharmaceutical compositions containing nalbuphine base withlong-acting effects and high bioavailability for oral administration aredesirable.

[0008] Recently, Yoa-Pu et al., U.S. Pat. No. 5,750,534 (the '534patent), disclose a nalbuphine prodrug which contains nalbuphinemonoester, wherein the R in the ester group (RCO) is a straight orbranched alkyl group of 2-36 carbon atoms or a phenyl group. Thenalbuphine monoester prodrug is characterized as having prolongedanalgesic duration. The '534 patent is herein incorporated by reference.

[0009] Hu et al., U.S. Pat. No. 6,225,321 (the '321 patent), discloseyet another nalbuphine prodrug which contains nalbuphine polyesterhaving a generic formula of R-[CO-NAL]_(n), wherein n is an integer from2-4 and R in the ester group is a saturated or nonosaturated,substituted or unsubstituted, aliphatic or aromatic group having 1 to 40carbon atoms. The nalbuphine polyester is designed as a soft drug whichcan maintain analgesic effect in animal body for 4-5 days. The '321patent is herein incorporated by reference.

[0010] In the sections to be presented below, the present inventionprovides a pharmaceutical composition which, by incorporating thenalbuphine ester prodrugs as described in the '534 patent and the '321patent as the active ingredient, together with an oily substance and asolubility-assisting agent, can be administered orally. Thepharmaceutical composition of the present invention not only provideslong-lasting effect but also demonstrates greater bioavailability forpain relief in animal body.

SUMMARY OF THE INVENTION

[0011] The present invention provides pharmaceutical compositions whichcontain (1) an active ingredient, which is a nalbuphine or a nalbuphineester prodrug, or the pharmaceutically acceptable salts of nalbuphine ornalbuphine ester prodrug; (2) an oily substance, and (3) asolubility-assisting agent. The pharmaceutical composition is preferablyadministered orally.

[0012] There are two kinds of nalbuphine ester prodrugs, which arenalbuphine monoester and nalbuphine polyester. Examples of nalbuphinemonoester include, but are not limited to, nalbuphine propionate,nalbuphine pivalate, nalbuphine enanthate, nalbuphine decanoate,nalbuphine behenate, nalbuphine erucicate, nalbuphine arachidate, andnalbuphine benzoate. Examples of nalbuphine polyester include, but arenot limited to, adipoyl dinalbuphine ester, sebacoyl dinalbuphine ester,1,3-cyclohexane diacid dinalbuphine ester, docosanodic dinalbuphineester, 3,3-dimethylglutaric diacid dinalbuphine ester, trinalbuphinetrimesoyl ester, 1,3,5-cyclohexane triacid trinalbuphine ester,pyromellitoyl tetranalbuphine ester. Among the nalbuphine esterprodrugs, sebacoyl dinalbuphine ester (SDN) is the most preferable oneto be used in oral administration.

[0013] The oily substance is preferably a vegetable oil, and morefavorably sesame oil, soybean oil or peanut oil. The most favorablevegetable oil is sesame oil. The solubility-assisting agent ispreferably benzyl benzoate.

[0014] The pharmaceutical composition of the present invention containsabout 1% to 15% by weight of free base or salts of nalbuphine ornalbuphine ester prodrug, preferably about 10% by weight; about 30% to90% by weight of the oily substance, preferably about 55% by weight ofsesame oil; and about 5% to 50% by weight of the solubility-assistingagent, preferably about 45% by weight of the solubility-assisting agent.

[0015] The present invention also provides a method for treatingpatients with severe, long lasting pain by orally administering thepharmaceutical composition described above to patients. The severe, longlasting pain suffered by patients is caused by cardiac, pulmonary,osteopathia, obstetrical surgery, burn injury, or terminal stage ofcancer.

[0016] The nalbuphine ester prodrug-containing oral pharmaceuticalcomposition demonstrates high bioavailability in vivo and prolongpain-killing effect. Also, because the pharmaceutical compositionprovided in the present invention can be administered orally, it is moreconvenient than the traditional use of nalbuphine, i.e., by injection orbuccal delivery.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 shows the nalbuphine concentration in blood plasma inbeagles after the pharmaceutical compositions were orally administeredinto the animals. •--• represents the group of animals (n=6)which weregiven the pharmaceutical composition containing (1) SDN, (2) sesame oil,and (3) benzyl benzoate; ▪--▪ represents the group of animals (n=6)which were given the pharmaceutical composition containing SDN powderonly; ▾--▾ represents the group of animals which were given thepharmaceutical composition containing SDN plus verapmail (n=6).

DETAILED DESCRIPTION OF THE INVENTION.

[0018] The present invention provides an oral pharmaceutical compositionwhich contains an effective amount of nalbuphine, nalbuphinederivatives, or pharmaceutically acceptable nalbuphine salts thereof.

[0019] Nalbuphine is a morphine derivative. Nalbuphine has the chemicalformula (I):

[0020] A nalbuphine monoester prodrug has the following generic chemicalformula (II):

[0021] in which R is R′CO, wherein R′ is a straight or branched alkylgroup of 2-36 carbon atoms or a phenyl group. (Yoa-Pu et al., U.S. Pat.No. 5,750,534).

[0022] The preferred nalbuphine monoester prodrugs which include, butare not limited to, nalbuphine propionate, nalbuphine pivalate,nalbuphine enanthate, nalbuphine decanoate, nalbuphine behenate,nalbuphine erucicate, nalbuphine arachidate, and nalbuphine benzoate.

[0023] A nalbuphine polyester prodrug has the following generic chemicalformula (III):

[0024] wherein n is an integer from 2 to 4 and wherein R is a saturatedor unsaturated, substituted or unsubstituted, aliphatic or aromaticgroup having 1 to 40 carbon atoms. (Hu et al., U.S. Pat. No. 6,225,321).

[0025] The preferred nalbuphine polyester prodrugs include adipoyldinalbuphine ester, sebacoyl dinalbuphine ester, 1,3-cyclohexane diaciddinalbuphine ester, docosanodic dinalbuphine ester, 3,3-dimethylglutaricdiacid dinalbuphine ester, trinalbuphine trimesoyl ester,1,3,5-cyclohexane triacid trinalbuphine ester, pyromellitoyltetranalbuphine ester. The most favorable nalbuphine polyester prodrugis sebacoyl dinalbuphine ester (SDN).

[0026] The pharmaceutical composition of the present invention containsthree major components: (1) an active ingredient; (2) an oily substance;and (3) a solubility-assisting agent.

[0027] The active ingredient of the pharmaceutical composition includesnalbuphine, nalbuphine monoester, and nalbuphine polyester, or apharmaceutically acceptable salts of nalbuphine, nalbuphine monoester,and nalbuphine polyester. The preferred active ingredient is nalbuphinepolyester. Among nalbuphine polyester, the most favorable one issebacoyl dinalbuphine ester.

[0028] The amount of nalbuphine or nalbuphine ester prodrug used in thepharmaceutical composition of the present invention is about 1% to 15%by weight of the composition. The preferred concentration of sebacoyldinalbuphine ester in the pharmaceutical composition of the presentinvention is 100 mg/ml.

[0029] The oily substance in the pharmaceutical composition of thepresent invention includes a vegetable oil. The vegetable oil used inthe present invention include, but are not limited to, sesame oil,soybean oil, peanut oil, or an ethyl ester of sesame oil, soybean oil,or peanut oil. The preferred oily substance is sesame oil. Thepharmaceutical composition contains about 30% to 90% by weight ofvegetable oil.

[0030] The solubility-assisting agent of the pharmaceutical compositionis benzyl benzoate. The pharmaceutical composition contains about 5% to50% by weight of the solubility-assisting agent.

[0031] Each and every one of these nalbuphine and/or nalbuphine esterprodrugs as listed above has been tested for suitability as an orallyadministered pharmaceutical composition for use in animals and humans.The efficacy and bioavailability of these nalbuphine ester prodrugs havebeen studied. The results indicate that the addition of thesolubility-assisting agent to the nalbuphine and/or nalbuphine esterprodrugs and an oily substance substantially improves thebioavailability and half-life of nalbuphine in blood.

[0032] Among the nalbuphine active ingredient, sebacoyl dinalbuphineester (SDN) appears to be the best in terms of longer half-life andgreater bioavailability rate. The studies using SDN as an example aretherefore provided below. Please note that the following examples areillustrative only, and should not be viewed as limiting the scope of thepresent invention. Reasonable variations, such as those occur toreasonable artisan, can be made herein without departing from the scopeof the present invention.

EXAMPLE 1 Preparation of the Pharmaceutical Composition

[0033] The pharmaceutical composition of the present invention isprepared as follows:

[0034] 1. Mixing 5.5 ml sesame oil with 4.5 ml benzyl benzoate andstirring well to form an oily mixture.

[0035] 2. Adding 1 g of SDN to 10 ml of the oily mixture with furtherstirring to produce a homogeneous pharmaceutical composition containingabout 100 mg SDN per ml of the oily mixture.

EXAMPLE 2 Comparative Studies of the Pharmaceutical Compositions inBeagles

[0036] Purpose:

[0037] To assess the effects of various pharmaceutical compositions ofthe present invention on beagles. The compositions were orallyadministered into beagles, and the concentration of nalbuphine in vivowas monitored in the animals as follows:

[0038] Method:

[0039] 1. Three pharmaceutical compositions were tested in this study,which include: (1) the pharmaceutical composition described in EXAMPLE 1(the “Complete SDN” group); (2) pure sebacoyl dinalbuphine ester powderwithout any oily substance or solubility-assisting agent (the “SDNPowder” group); and (3) sebacoyl dinalbuphine ester with verapamil(which is used as an oily substance) (the “SDN +Verapamil” group).

[0040] 2, In each study group, the pharmaceutical composition thatcontained 30 mg/kg of SDN were orally given to beagles.

[0041] 3. Blood samples were taken from the forearm vein at 0.167, 0.33,0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 30, and 48 hours after theoral administration.

[0042] 4. The blood samples were analyzed by high performance liquidchromatography (HPLC) to determine the pharmacokinetics (including thehalf-life and bioavailability of nalbuphine) in vivo.

[0043] Result:

[0044] As shown in FIG. 1, the concentration of nalbuphine in the threegroups peaked about 1-2 hours after oral administration of thepharmaceutical compositions. Among the three groups, both the CompleteSDN group and the SDN+Verapamil group had about the same concentrationof nalbuphine in plasma 1-3 hours after the oral uptake of SDN. Theconcentration of nalbuphine in the SDN powder was much less than theother two groups. However, the concentration of nalbuphine in the SDNpowder and the SDN+verapamil group decreased substantially whereas theconcentration of nalbuphine in the Complete SDN group still maintainedat high percentage.

[0045] Verapamil isα-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl)-benzeneacetonitrile.It is a viscous, pale yellow oil. Verapamil is a well-known cytochromeP₄₅₀ 3A (CYP 3A) inhibitor.

[0046] CYP 3A is known to be responsible for metabolism of a largenumber of drugs in vivo, thus, reducing the bioavailability of drugs.The drugs that are know to be affected by CYP 3A include nifedipine,macrofide antibiotics such as erythromycin and troleandomycin,cyclosporin, FK506, teffenadine, tamoxifen, lidocaine, midazolam,triazolam, dapsone, diltiazem, lovastatin, quinidine, ethylestradiol,testosterone, and alfentanil. A CYP 3A inhibitor can be used to inhibitthe enzymatic activity of CYP 3A and thus improve the bioavailability ofthe drugs.

[0047] Assuming that the bioavailability of nalbupine is also affectedby CYP 3A, an inclusion of verapamil (the CYP 3A inhibitor), togetherwith SDN, should further improve the bioavailability of nalbupine (ifthere is an synergistic effect between verapamil and SDN).

[0048] The results in FIG. 1 suggest that without thesolubility-assisting agent (benzyl benzoate), the addition of verapamildid not improve the bioavailability of nalbupine.

[0049] Table 1 shows the results of the pharmacokinetic studies of thethree pharmaceutical compositions. TABLE 1 Pharmacokinetics ofNalbuphine in Beagles Nalbuphine Complete SDN SDN Powder SDN + VerapamilPharmcokinetics Group Group Group Nalbuphine Half- 23.9 ± 3.0  8.1 ± 1.6 9.5 ± 2.3 Life (hrs) AUC/Dose  171 ± 18   39 ± 11   83 ± 22 (h * ng *kg/ml/mg) Bioavailability 67.1 ± 4.3 14.6 ± 4.0 30.0 ± 8.0 (%)

[0050] As shown in Table 1, the nalbuphine half-life (t_(1/2)) in theComplete SDN group is 23.9±3.0 hours, which was about 3 times longerthan that of the SDN powder group and about 2.5 times longer than thatof the SDN+Verapamil group. The bioavailability of nalbuphine, asdetermined by AUC (area under curve) and by % of decrease (%bioavailability) also shows that the Complete group is far much betterthan the rest of the two group (AUC-171 [Complete Group] vs. 39 [SDNPowder Group] or 83 [SDN+Verapamil Group]; % bioavailability: 67%[Complete Group] vs. 14.6[SDN Powder Group] or 30.0 [SDN+VerapamilGroup]).

[0051] The results of FIG. 1 and Table 1 show that the addition of anoily substance to SDN greatly improve the half-life and bioavailabilityof nalbuphine in plasma (as comparing the SDN Powder Group andSDN+verapamil Group). But the half-life and bioavailability rate ofnalbuphine is far much greater when benzyl benzoate as asolubility-assisting agent is added to SDN with oil (as comparing theComplete SDN Group with the SDN Powder Group and SDN+verapamil Group).

[0052] While the invention has been described by way of examples and interms of the preferred embodiments, it is to be understood that theinvention is not limited to the disclosed embodiments. On the contrary,it is intended to cover various modifications as would be apparent tothose skilled in the art. Therefore, the scope of the appended claimsshould be accorded the broadest interpretation so as to encompass allsuch modifications.

We claim:
 1. A pharmaceutical composition comprising: as an activeingredient, an effective amount of free base or pharmaceuticallyacceptable salts of nalbuphine or nalbuphine ester; an oily substance;and a solubility-assisting agent; wherein said pharmaceuticalcomposition is an orally administered composition.
 2. The pharmaceuticalcomposition according to claim 1, wherein said nalbuphine ester isnalbuphine monoester or nalbuphine polyester.
 3. The pharmaceuticalcomposition according to claim 2, wherein said nalbuphine monoester isat least one selected from the group consisting of nalbuphinepropionate, nalbuphine pivalate, nalbuphine enanthate, nalbuphinedecanoate, nalbuphine erucicate, nalbuphine arachidate, and nalbuphinebenzoate.
 4. The pharmaceutical composition according to claim 2,wherein said nalbuphine polyester is at least one selected from thegroup consisting of adipoyl dinalbuphine ester, sebacoyl dinalbuphineester, 1,3-cyclohexane diacid dinalbuphine ester, docosanodicdinalbuphine ester, 3,3-dimethylglutaric diacid dinalbuphine ester,trinalbuphine trimesoyl ester, 1,3,5-cyclohexane triacid trinalbuphineester, and pyromellitoyl tetranalbuphine ester.
 5. The pharmaceuticalcomposition according to claim 2, wherein said nalbuphine polyester issebacoyl dinalbuphine ester (SDN).
 6. The pharmaceutical compositionaccording to claim 1, wherein said oily substance is vegetable oil. 7.The pharmaceutical composition according to claim 6, wherein saidvegetable oil is sesame oil.
 8. The pharmaceutical composition accordingto claim 1, wherein said solubility-assisting agent is benzyl benzoate9. The pharmaceutical composition according to claim 1, wherein saidnalbuphine ester is about 1% to 15% by weight of said composition. 10.The pharmaceutical composition according to claim 9, wherein saidnalbuphine ester is about 10% by weight of said composition.
 11. Thepharmaceutical composition according to claim 1, wherein said oilysubstance is about 30% to 90% by weight of said composition.
 12. Thepharmaceutical composition according to claim 9, wherein said whereinsaid oil substance is about 55% by weight of the composition.
 13. Thepharmaceutical composition according to claim 1, wherein saidsolubility-assisting agent is about 5% to 50% by weight of thecomposition.
 14. The pharmaceutical composition according to claim 11,wherein said solubility-assisting agent is about 45% by weight of saidcomposition.
 15. A method for treating patients with pain comprisingorally administering the pharmaceutical composition according to claim 1to patients.
 16. The method according to claim 15, wherein said pain iscaused by at least one selected from the group consisting of cardiacsurgery, pulmonary surgery, osteopathia surgery, obstetrical surgery,burn injury, and terminal stage of cancer.
 17. An analgesic agentcomprising the pharmaceutical composition of claim 1.